JP2009263283A - Hepatitis c virus inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an HCV inhibitor effective for prophylaxis or therapy of hepatitis C. <P>SOLUTION: This hepatitis C virus inhibitor contains a compound expressed by general formula (I), wherein X is O, S, N or C; R1 and R2 are same or different, and each represents a hydrogen atom, a halogen atom, a linear or branched saturated or unsaturated aliphatic hydrocarbon group or an optional group selected from the group consisting of a cycloalkyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, aralkyl, etc., and an aliphatic heterocycle each may bear substituent(s). <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to hepatitis C virus inhibitors. More specifically, the present invention relates to a novel hepatitis C virus inhibitor detected by searching for various substances that affect hepatitis C virus infection, replication, or translation of hepatitis C virus protein.

  Hepatitis C virus (hereinafter referred to as “HCV”) was discovered and identified in 1989 as a causative virus for non-A non-B hepatitis. HCV is an RNA virus with an envelope. The genome is single-stranded plus-strand RNA and is classified into the genus Hepacivirus of the Flaviviridae family (from The International Committee on Taxonomy of Viruses of the International Union of Microbiological Societies).

  Even with the same hepatitis virus, the DNA virus, hepatitis B virus (HBV), is excluded by the immune mechanism and ends with an acute infection, even if it is infected, except in immature newborns and infants. In comparison, HCV circumvents the host's immune mechanism for reasons that are not yet clear. Therefore, even when an adult with a developed immune system is infected, it often shifts to persistent infection.

Hepatitis caused by HCV infection (hepatitis C) can lead to cirrhosis and eventually liver cancer over the course of more than 20 years. It is known that even if liver cancer is removed by surgery, there are many patients whose liver cancer recurs due to inflammation that continues in the non-cancerous part.
In addition, it has been reported that HCV infection is involved in skin diseases such as chronic urticaria, lichen planus and cryoglobulinemia purpura (Nichishikai, 111 (7), 1075-81, 2001).

  It is estimated that there are about 2 million HCV infected people in Japan and about 200 million people worldwide. There are also many so-called asymptomatic carriers who are not aware of being infected with HCV. Currently, in Japan, about 35,000 people suffer from hepatocellular carcinoma annually, 80% of which are due to HCV infection.

  Currently, combination therapy of interferon and ribavirin (1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) is common for HCV infection. However, this combination therapy is effective only for 50% of all patients and is known to cause serious side effects such as cytopenia and hemolytic anemia.

  Under such circumstances, it is required to detect an HCV inhibitor having excellent medicinal effects. Therefore, it is required to clarify the details of the life cycle of HCV, such as how HCV replicates and proliferates and how it affects host cells.

  In 1999, the HCV replicon system appeared as an experimental system for artificially proliferating HCV. In this system, NS3 to NS5B regions essential for HCV genome replication and the HCV subgenome consisting of both ends of the genome are replicated in the cell, and the number of copies of HCV subgenome per cell is several thousand. To reach.

In addition, HCV replicon systems that synthesize RNA of infectious clones using T7 RNA polymerase have also been reported (Non-patent Documents 1 and 2 and Patent Document 1).
However, the HCV inhibitor detected from this replicon system is only an inhibitor that acts in the late stage after HCV infection, and is not sufficient as a medicinal effect.

International Publication WO05 / 028652 Nature Medicine 11, Number 7, July p.791-796 (2005) Virus Volume 55 Issue 2 pp.287-296 (2005)

  The present invention has been made in view of such problems, and an object of the present invention is to provide an HCV inhibitor having high inhibitory activity against HCV proliferation, targeting any one of the entire processes of the growth ring. Is. Another object of the present invention is to provide a drug effective for the prevention or treatment of hepatitis C.

In order to achieve the above object, the HCV inhibitor according to the present invention comprises:
A hepatitis C virus inhibitor capable of suppressing infection or production of hepatitis C virus in a host cell, comprising at least one of the compounds represented by the following general formulas (I) to (VIII).

Formula (I)

Formula (II)

Formula (III)

Formula (IV)

General formula (V)

Formula (VI)

Formula (VII)

Formula (VIII)

  In the general formulas (I) to (VIII), X is O, S, N, or C, and R1, R2, and R3 are the same or different and are each a hydrogen atom, a halogen atom, a linear or branched group A saturated or unsaturated aliphatic hydrocarbon group, an optionally substituted cycloalkyl group, an aryl group, a heteroaryl group, an arylcarbonyl group, a heteroarylcarbonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkyl group; Any group selected from the group consisting of a group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group, an aralkyloxycarbonyl group, an allyl ether group, a cycloether group, and an aliphatic heterocycle It is.

  Further, the compound represented by the general formula (I) may be a compound represented by the following structural formula (IX).

Structural formula (IX)

  The compound represented by the general formula (III) may be a compound represented by the following structural formula (XII).

Structural formula (XII)

  Further, the compound represented by the general formula (IV) may be a compound represented by the following structural formula (XIII).

Structural formula (XIII)

  In addition, the compound represented by the general formula (V) may be a compound represented by the following structural formula (XIV).

Structural formula (XIV)

  The compound represented by the general formula (VI) may be a compound represented by the following structural formula (XIX).

Structural formula (XIX)

  In addition, the compound represented by the general formula (VII) may be a compound represented by the following structural formula (XX).

Structural formula (XX)

  It is also possible that the compound represented by the general formula (VIII) is a compound represented by the following structural formula (XXII).

Structural formula (XXII)

  The HCV inhibitor according to the present invention is an effective drug for the prevention or treatment of hepatitis C.

[HCV inhibitor]
As a result of intensive studies conducted by the present inventors, the compounds represented by the above general formulas (I) to (VIII) from the compound libraries containing pure natural products derived from plants and microorganisms, and their pharmaceutically acceptable compounds. The present inventors have found that an HCV inhibitor containing at least one of a salt and a solvate is an HCV inhibitor that targets any one of the entire processes of the growth ring.

  In the above general formulas (I) to (VIII), a cycloalkyl group, an aryl group, a heteroaryl group, an arylcarbonyl group, a heteroarylcarbonyl group, an arylsulfonyl group, a heteroarylsulfonyl group which may have a substituent. , An aralkyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group, an aralkyloxycarbonyl group, an allyl ether group, a cycloether group, and an aliphatic heterocycle, Group, lower alkylcarbonyl group, lower alkylsulfonyl group, lower alkoxy group, hydroxyl group, halogen atom, haloalkyl group, amino group, substituted amino group, cyano group, nitro group, carboxy group, carbamoyl group, sulfate group, sulfite group, etc. included.

  Aryl is phenyl, naphthyl, or a polycyclic aromatic hydrocarbon group (such as phenanthryl).

  Heteroaryl is a 5- to 6-membered aromatic ring group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S (for example, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole) Pyridine, pyridazine, pyrimidine, pyrazine, triazine).

  Arylcarbonyl is a group formed by substituting the above aryl for a carbonyl group.

  Heteroarylcarbonyl is a group formed by substituting the above heteroaryl for a carbonyl group.

  Arylsulfonyl is a group formed by substituting the above aryl for a sulfonyl group.

  Heteroarylsulfonyl is a group formed by substituting the above heteroaryl for a sulfonyl group.

  Aralkyl is a group formed by substituting the above aryl with a lower alkyl group described later, and includes benzyl, methylbenzyl, naphthylmethyl, and the like.

  Aralkyloxycarbonyl is a group formed by bonding the above aralkyl to a carbonyl group via an O atom, such as benzyloxycarbonyl.

  The aliphatic heterocycle is a 5- to 6-membered aliphatic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and is pyrrolidinyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, Examples include morpholinyl, thiomorpholinyl, pyrrolyl, thiazolyl and the like.

  Lower alkyl is a linear or branched alkyl group having 1 to 8 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl , Octyl and the like.

  Lower alkoxy is a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like. .

  Halogen is, for example, fluorine, chlorine, bromine or iodine.

  Lower alkylcarbonyl is a group formed by substituting the above lower alkyl with a carbonyl group.

  Lower alkylsulfonyl is a group formed by substituting the above lower alkyl with a sulfonyl group.

  Examples of pharmaceutically acceptable salts include those shown below. Examples of the basic addition salt include alkali metal salts such as sodium salt and potassium salt. Further, there are alkaline earth metal salts such as calcium salts and magnesium salts. Further, for example, there is an ammonium salt. Examples thereof include aliphatic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, and brocaine salt. Further, there are aralkylamine salts such as N, N-dibenzylethylenediamine. Examples thereof include heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, and isoquinoline salt. Examples thereof include quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, and tetrabutylammonium salt. In addition, there are basic amino acid salts such as arginine salt and lysine salt.

  Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and perchlorate. Examples thereof include organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, and ascorbate. Examples thereof include sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate. Examples thereof include acidic amino acids such as aspartate and glutamate.

  In the present embodiment, the host cell refers to a cell that can be infected by HCV, and includes, for example, a hepatocyte.

  The HCV inhibitor according to this embodiment contains a pharmaceutically effective amount of at least one compound of the general formulas (I) to (VIII) shown above, and further includes a pharmaceutically acceptable carrier. Things are also included.

  The compounds of the general formulas (I) to (VIII), pharmaceutically acceptable salts and solvates thereof are prepared according to conventional methods, and include excipients, binders, disintegrants, lubricants, flavoring agents, and solubilizing agents. , Formulated into dosage forms suitable for oral administration, intra-tissue administration, topical administration, rectal administration, etc., using known adjuvants that can be generally used in the pharmaceutical formulation technical field such as suspensions, coatings, etc. can do. In addition to the above-mentioned auxiliary agents, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents, and other auxiliary agents as well as other pharmaceuticals may be included as necessary.

  Examples of dosage forms suitable for oral administration include tablets, dragees, pills, capsules, drops, sublinguals, powders, powders, liquids for drinking, and other dosage forms. Furthermore, the tablet can be made into a tablet coated with a normal coating, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric tablet, a film-coated tablet, a double tablet, or a multilayer tablet as necessary. When preparing into the form of a tablet, a conventionally well-known thing can be widely used as a carrier in this field | area. Examples of such carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose solution, Binders such as starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, Disintegrating agents such as sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil; absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; Serine, moisturizing agents such as starch; starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid; purified talc, stearates, boric acid powder, such as lubricants such as polyethylene glycol can be exemplified.

  In preparing the pill form, a wide variety of carriers conventionally known in this field can be used. Examples of such carriers include excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; disintegration such as laminaran agar An agent etc. can be illustrated. These preparations for oral administration can be administered in solid, powder or liquid dosage units.

  Examples of dosage forms suitable for intra-tissue administration include injections. When prepared as an injection, it can be in the form of a solution, emulsion, suspension or the like. They are preferably sterilized and isotonic with blood. In preparing in the form of these solutions, emulsions and suspensions, those conventionally used in this field as diluents can be used. As such a diluent, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. A sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution, and usual solubilizers, buffers, pH adjusters, soothing agents, and the like can also be blended. These solutions, emulsions and suspensions are prepared from a certain amount of the pharmaceutically acceptable salts and solvates of the compounds of general formulas (I) to (VIII), as described above for aqueous and oily non-toxic diluents. It is possible to prepare it by dissolving or suspending it in the solution, and further adding an isotonic agent or the like, if necessary, and sterilizing. These injections can be administered subcutaneously, intramuscularly or intravenously.

  Examples of dosage forms suitable for topical administration include topical preparations such as topical solutions, creams, powders, pastes, gels and ointments. These are compounds of the general formulas (I) to (VIII), pharmaceutically acceptable salts and solvates thereof, fragrances, colorants, fillers, surfactants, moisturizing agents that meet the purpose of external preparations. It can be prepared by combining with one or more of agents, emollients, gelling agents, carriers, preservatives, stabilizers and the like.

  Suppositories can be mentioned as dosage forms suitable for rectal administration. In preparing a suppository, a variety of conventionally known base materials in this field can be used. Examples of such a substrate include low-melting-point substrates such as higher esters such as myristic palmitate, higher alcohols, polyethylene glycol, cocoa butter, gelatin, semi-synthetic glycerides, and mixtures thereof. Suppositories can be prepared by mixing a certain amount of the pharmaceutically acceptable salts and solvates of the compounds of the general formulas (I) to (VIII) into the above-mentioned base material and molding the mixture.

  The pharmaceutical composition is preferably administered in dosage unit form, and is administered orally, intra-tissue (subcutaneous, intramuscular, intravenous, etc.), topical (transdermal etc.) or rectally. can do. Of course, the pharmaceutical composition is administered in a dosage form suitable for these administration methods.

  When the pharmaceutically acceptable salts and solvates of the compounds of the general formulas (I) to (VIII) are administered as pharmaceuticals, the dosage as an antiviral agent is determined by the patient's condition such as age and weight, administration route, disease The amount of active ingredient is usually in the range of 1 to 2000 mg per day for human adults. Depending on the patient's condition and the like, a dose below or above the above range can also be administered. When administering a large amount, it is desirable to divide the dose into several times a day.

[Method for detecting HCV inhibitor]
As shown in FIG. 1, the HCV inhibitor according to the present embodiment first measures the HCV concentration (that is, the number of HCVcores) after contacting human hepatoma-derived Huh7 cells, a test sample and infectious HCV. Thus, a substance that affects HCV replication or HCV protein translation is selected as a candidate.

  Candidates are selected such that the survival rate (survival rate (%)) of human hepatoma-derived Huh7 cells is not less than a certain value and the number of HCV cores (fmol / ml) is not more than a certain value.

Next, of the selected candidate compounds, a compound having a selectivity (selective index) of a certain value or more is detected as a novel HCV inhibitor.
Here, the selective index is CC ₅₀ / EC ₅₀ . CC ₅₀ is the concentration of drug at which cells are 50% damaged. The EC ₅₀ value is the concentration of drug that inhibits virus growth by 50%.

Hereinafter, a method for detecting an HCV inhibitor will be described in detail.
First, Huh7.5. 1 cells are used as human hepatoma-derived Huh7 cells. Then, Huh7.5. 1 cells are suspended in the cell culture medium and seeded in a screening container. The cells used preferably have passage numbers up to the 43rd.

  Next, a screening candidate compound as a test sample is added to a screening container containing cells.

Next, infectious HCV is seeded, replicating cells containing the screening candidate compound and infectious HCV are cultured, and infectious HCV is detected in the resulting culture.
Infectious HCV can be prepared from a host cell into which a plasmid vector containing an infectious HCV replicon as shown in FIG. 2 is introduced using cDNA of JFH1 strain.

  A plasmid vector containing an infectious HCV replicon contains at least a core protein, two envelope proteins (E1, E2) and a p7 protein, and nonstructural proteins (NS2, NS3, NS4, NS5) necessary for replication, and contains the HCV. A plasmid vector containing a constituting genome, that is, an infectious HCV replicon, has a promoter sequence arranged upstream of a sequence encoding a core protein.

  The promoter sequence is not particularly limited as long as the promoter sequence is arranged so that HCV can exhibit autonomous replication ability in human hepatoma-derived Huh7 cells, but a PolI promoter sequence is preferably used.

  In addition to the above sequences, a plasmid vector containing an infectious HCV replicon may have a terminator sequence located downstream of, for example, a sequence encoding an NS protein, and preferably includes a PolI terminator sequence. Furthermore, one IRES sequence may be included upstream of the sequence encoding the core protein, and one selectable marker gene or reporter gene may be further included therein.

  Next, in order to culture infectious HCV in the cells, the cells are heated at 37 ± 1 ° C. for 3 to 10 days, preferably 4 to 7 days, more preferably 5 to 6 days.

Next, after the above culture, the relationship between the survival rate of human hepatoma-derived Huh7 cells (survival rate (%)) and the number of HCV cores (fmol / ml) is determined.
A compound having an HCV core of 20000 fmol / ml or less and a survival rate of 65% or more is selected.

Next, after culturing using the culture supernatant, the amount of HCV core protein in the supernatant is quantified by an ortho HCV antigen ELISA test, and the HCV proliferation inhibitory effect of each compound is evaluated. An EC ₅₀ value is determined from the HCV growth inhibitory effect.

Next, in addition to the screening method described above, in order to more reliably confirm the influence of the candidate compound on the promotion or suppression of HCV replication, in order to eliminate non-specific effects, as shown in FIG. In addition, a cytotoxicity test is performed.
Each compound is tested for cytotoxicity against Huh7.5.1 cells by the WST method in which the absorbance of formazan produced by the tetrazolium salt WST-8 is directly measured. The CC ₅₀ value is determined from the cytotoxicity test result.

Then, the selectivity of the compound selected as a candidate is measured. Selectivity represents the ratio of cytotoxicity to the effective concentration of a drug, and the higher the value, the better the drug concentration or the higher the concentration range that can be used safely as a drug.
A compound having a selectivity of 10.0 or more is detected as a hepatitis C virus inhibitor.

[Other Embodiments]
In addition to the compounds shown in (I) to (VIII), the compound contained in the HCV inhibitor includes L-form, D-form, or racemate in the presence of optical isomers. In addition, the compounds represented by (I) to (VIII) can be further chemically modified to be derivatized to another compound.

  Huh7.5. 1 cells were used as Huh7 cells derived from human liver cancer. Then, Huh7.5. 1 cells were suspended in the cell culture medium and seeded in a screening container such as a 96-well microplate.

  Next, a screening candidate compound as a test sample was added to a screening container containing cells. As a screening candidate compound, a pure natural product compound library derived from plants and microorganisms (Analytical Library of Enamine (Namiki Corporation)) was used, and 3215 was used as the item.

Next, infectious HCV was seeded, replicating cells containing the screening candidate compound and infectious HCV were cultured, and infectious HCV was detected in the resulting culture.
Infectious HCV is a plasmid vector (pHH) containing the infectious HCV replicon shown in FIG. 2 containing cDNA of JFH1 strain (genotype 2a) using RNA PolI promoter / terminator system according to the method described in International Publication WO07 / 037428. / ZeoJFH1) was constructed, and this plasmid vector was prepared using a cell line (Huh7.5.1 / JFH1zeo R cell) introduced into Huh7.5.1 cells derived from human liver cancer.

  The infectious HCV was then warmed at 37 ± 1 ° C. for 6 days to culture in cells.

Next, after the culture, the relationship between the survival rate of human hepatoma-derived Huh7 cells (survival rate (%)) and the number of HCV cores (fmol / ml) was determined.
The relationship between the survival rate of human hepatoma-derived Huh7 cells (survival rate (%)) and the number of HCV cores (fmol / ml) is shown in FIG.
A compound having an HCV core of 20000 fmol / ml or less and a survival rate of 65% or more is indicated by a triangle in the region surrounded by a solid line in FIG. Here, 53 candidate compounds were detected.

Next, the HCV growth inhibitory effect of each compound was evaluated. In the evaluation, the concentration of HCV was measured by the screening shown in FIG. 1, and the EC ₅₀ value was determined from the HCV growth inhibitory effect.
Further, a cytotoxicity test for Huh7.5.1 cells was performed by the WST method shown in FIG. And from the cell toxicity test results were determined _{CC 50} values.

The selectivity of compounds selected as candidates was measured, and 14 compounds having a CC ₅₀ / EC ₅₀ of 10 or more were selected as shown in the following structural formulas (IX) to (XXII). These compounds according to structural formulas 1 to 14 are indicated by circles in FIG.

  The compound according to Structural Formula (IX) was shown below.

Structural formula (IX)

  The compound represented by the structural formula (IX) is a compound represented by the general formula (I), wherein R1 is represented by the formula (a), R2 is represented by the formula (b), and X is represented by N. .

Formula (a)

Formula (b)

The compound represented by the structural formula (IX) had a CC ₅₀ of 9.88 μM, an EC ₅₀ of 0.50 μM, and a CC ₅₀ / EC ₅₀ of 19.05.

  Next, the compound according to Structural Formula (X) was shown below.

Structural formula (X)

  The compound represented by the structural formula (X) was a compound represented by the general formula (II) in which R1 was represented by the formula (c).

Formula (c)

The compound represented by the structural formula (X) had a CC ₅₀ of at least 60 μM or more, an EC ₅₀ of 5.88 μM, and a CC ₅₀ / EC ₅₀ of at least 10.2.

  Next, the compound according to Structural Formula (XI) was as shown below.

Structural formula (XI)

  The compound represented by the structural formula (XI) is a compound represented by the general formula (III), wherein R1 is the formula (d), R2 is the formula (e), and X is O. .

Formula (d)

Formula (e)

The compound represented by Structural Formula (XI) had a CC ₅₀ of at least 50 μM or more, an EC ₅₀ of 1.44 μM, and a CC ₅₀ / EC ₅₀ of at least 34.7 or more.

  Next, the compound according to Structural Formula (XII) was shown below.

Structural formula (XII)

  The compound represented by the structural formula (XII) is a compound represented by the general formula (III), wherein R1 is the formula (f), R2 is the formula (e), and X is O. .

Formula (f)

In the compound represented by Structural Formula (XII), CC ₅₀ was 10.3 μM, EC ₅₀ was 0.30 μM, and CC ₅₀ / EC ₅₀ was 34.3.

  The compound according to Structural Formula (XIII) was shown below.

Structural formula (XIII)

  The compound represented by the structural formula (XIII) was a compound represented by the general formula (IV), in which R1 was represented by the formula (g) and R2 was represented by the formula (h).

Formula (g)

Formula (h)

In the compound represented by the structural formula (XIII), CC ₅₀ was 11.2 μM, EC ₅₀ was 0.19 μM, and CC ₅₀ / EC ₅₀ was 58.9.

  The compound according to Structural Formula (XIV) was shown below.

Structural formula (XIV)

  The compound represented by the structural formula (XIV) is a compound represented by the general formula (V), wherein R1 is represented by the formula (e), R2 is represented by the formula (i), and R3 is represented by the formula (j). Met.

Formula (i)

Formula (j)

The compound represented by the structural formula (XIV) had a CC ₅₀ of 15.2 μM, an EC ₅₀ of 0.43 μM, and a CC ₅₀ / EC ₅₀ of 35.3.

  The compound according to Structural Formula (XV) was shown below.

Structural formula (XV)

The compound represented by the structural formula (XV) is a compound represented by the general formula (V), in which —CH ₂ N (R1) R2 is represented by the formula (k) and R3 is represented by the formula (l). there were.

Formula (k)

Formula (l)

The compound represented by the structural formula (XV) had a CC ₅₀ of 13.0 μM, an EC ₅₀ of 0.91 μM, and a CC ₅₀ / EC ₅₀ of 14.2.

  The compound according to Structural Formula (XVI) was shown below.

Structural formula (XVI)

  The compound represented by the structural formula (XVI) is a compound represented by the general formula (VI), wherein R1 is the formula (m), R2 is the formula (e), R3 is the formula (n), and X is N. , Was represented.

Formula (m)

Formula (n)

The compound represented by the structural formula (XVI) had a CC ₅₀ of 13.7 μM, an EC ₅₀ of 1.15 μM, and a CC ₅₀ / EC ₅₀ of 11.9.

  The compound according to Structural Formula (XVII) was as shown below.

Structural formula (XVII)

  The compound represented by the structural formula (XVII) is a compound represented by the general formula (VI), in which R1 is the formula (o), R2 is the formula (e), R3 is the formula (p), and X is N. , Was represented.

Formula (o)

Formula (p)

In the compound represented by the structural formula (XVII), CC ₅₀ was 13.8 μM, EC ₅₀ was 1.35 μM, and CC ₅₀ / EC ₅₀ was 10.2.

  The compound according to the structural formula (XVIII) was as shown below.

Structural formula (XVIII)

  The compound represented by the structural formula (XVII) is a compound represented by the general formula (VI), in which R1 is the formula (m), R2 is the formula (e), R3 is the formula (q), and X is N. , Was represented.

Formula (q)

The compound represented by the structural formula (XVIII) had a CC ₅₀ of 12.7 μM, an EC ₅₀ of 1.07 μM, and a CC ₅₀ / EC ₅₀ of 11.8.

  The compound according to Structural Formula (XIX) was shown below.

Structural formula (XIX)

  The compound represented by the structural formula (XIX) is a compound represented by the general formula (VI), in which R1 is the formula (r), R2 is the formula (e), R3 is the formula (s), and X is C. , Was represented.

Formula (r)

Formula (s)

In the compound represented by the structural formula (XIX), CC ₅₀ was 13.0 μM, EC ₅₀ was 0.19 μM, and CC ₅₀ / EC ₅₀ was 68.4.

  The compound according to Structural Formula (XX) was shown below.

Structural formula (XX)

  The compound represented by the structural formula (XX) is a compound represented by the general formula (VII), in which R1 is represented by the formula (e), R2 is represented by the formula (t), and R3 is represented by the formula (u). Met.

Formula (t)

Formula (u)

The compound represented by the structural formula (XX) had a CC ₅₀ of at least 50 μM or more, an EC ₅₀ of 0.61 μM, and a CC ₅₀ / EC ₅₀ of at least 81.9 or more.

  The compound according to Structural Formula (XXI) was shown below.

Structural formula (XXI)

  The compound represented by the structural formula (XXI) is a compound represented by the general formula (VII) in which -N-R1 (-R2) is represented by the formula (v) and R3 is represented by the formula (w). there were.

Formula (v)

Formula (w)

In the compound represented by the structural formula (XXI), CC ₅₀ was 14.1, EC ₅₀ was 1.27 μM, and CC ₅₀ / EC ₅₀ was 11.1.

  The compound according to Structural Formula (XXII) was shown below.

Structural formula (XXII)

  The compound represented by the structural formula (XXII) was a compound represented by the general formula (VIII), in which R1 is represented by the formula (x) and R2 is represented by H.

Formula (x)

In the compound represented by the structural formula (XXII), CC ₅₀ was 15.2, EC ₅₀ was 0.88 μM, and CC ₅₀ / EC ₅₀ was 17.2.

The CC ₅₀ , EC ₅₀ , and CC ₅₀ / EC ₅₀ for structural formulas (IX) to (XXII) are shown in Table 1 below.

For those having an EC ₅₀ of 1.0 μM or less, Structural Formula (IX), Structural Formula (XII), Structural Formula (XIII), Structural Formula (XIV), Structural Formula (XV), Structural Formula (XIX), Structural Formula ( XX) and structural formula (XXII). These compounds are considered to have a high HCV inhibitory effect.

  The present invention can be used as an effective drug for the prevention or treatment of hepatitis C.

It is a figure which shows the assay method which concerns on embodiment. It is a figure which shows the structure of the HCV replicon genome and expression plasmid which concern on embodiment. It is a figure which shows the relationship between the density | concentration of HCV core, and a survival rate. It is a figure which shows a compound with high selectivity in the relationship between the density | concentration of HCV core, and a survival rate.

Claims (8)

A hepatitis C virus inhibitor capable of suppressing infection or production of hepatitis C virus in a host cell, comprising at least one of the compounds represented by the following general formulas (I) to (VIII).
Formula (I)

Formula (II)

Formula (III)

Formula (IV)

General formula (V)

Formula (VI)

Formula (VII)

Formula (VIII)

(Wherein X is O, S, N, or C, and R1, R2, and R3 are the same or different and are a hydrogen atom, a halogen atom, a linear or branched saturated or unsaturated aliphatic group, Hydrocarbon group, cycloalkyl group optionally having substituent (s), aryl group, heteroaryl group, arylcarbonyl group, heteroarylcarbonyl group, aryl sulfonyl group, heteroaryl sulfonyl group, aralkyl group, alkyloxy group, alkenyl It is an arbitrary group selected from the group consisting of an oxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group, an aralkyloxycarbonyl group, an allyl ether group, a cycloether group, and an aliphatic heterocycle. The hepatitis C virus inhibitor according to claim 1, wherein the compound represented by the general formula (I) is a compound represented by the following structural formula (IX).
Structural formula (IX)

The hepatitis C virus inhibitor according to claim 1 or 2, wherein the compound represented by the general formula (III) is a compound represented by the following structural formula (XII).
Structural formula (XII)

The hepatitis C virus inhibitor according to any one of claims 1 to 3, wherein the compound represented by the general formula (IV) is a compound represented by the following structural formula (XIII).
Structural formula (XIII)

The hepatitis C virus inhibitor according to any one of claims 1 to 4, wherein the compound represented by the general formula (V) is a compound represented by the following structural formula (XIV).
Structural formula (XIV)

The hepatitis C virus inhibitor according to any one of claims 1 to 5, wherein the compound represented by the general formula (VI) is a compound represented by the following structural formula (XIX).
Structural formula (XIX)

The hepatitis C virus inhibitor according to any one of claims 1 to 6, wherein the compound represented by the general formula (VII) is a compound represented by the following structural formula (XX).
Structural formula (XX)

The hepatitis C virus inhibitor according to any one of claims 1 to 7, wherein the compound represented by the general formula (VIII) is a compound represented by the following structural formula (XXII).
Structural formula (XXII)

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